PROJECT SUMMARY Low- and middle-income countries are projected to have substantial increases in incidence of type 2 diabetes mellitus, the same regions where tuberculosis (TB) is endemic and a public health priority. Diabetes increases the risk of TB disease by three times and an estimated 15% of incident TB cases are due to diabetes, similar to the proportion of TB cases attributable to HIV. In the context of increasing rates of co-occurring TB and diabetes, prevention efforts to reduce the burden of dual disease are severely limited by critical gaps in knowledge of the relationship between latent TB infection and risk of diabetes mellitus. The specific aims of this proposal are to: (1) determine the extent to which latent TB infection (measured by interferon-gamma release assay [IGRA]) increases the risk of incident type 2 diabetes mellitus; (2) determine if latent TB increases the risk of progression from normal blood glucose to pre-diabetes; and (3) determine the extent to which latent TB treatment decreases the risk of incident type 2 diabetes among patients with latent TB infection. The aims of this project will be achieved by building a large database of patients with known latent TB infection status who are at risk of developing diabetes. The study will use longitudinal data from the Veterans Affairs Corporate Data Warehouse from 2000-2015 to build a retrospective cohort of more than 100,000 patients. The analysis will include multiple modeling strategies and propensity scores to assess the relationship between latent TB infection and rate of incident diabetes. This research has the potential to have far-reaching implications for biomedical approaches to diabetes prevention and TB control. The proposed study includes an unprecedented hypothesis that challenges current assumptions and the paradigm that the observed association between active TB and diabetes is singularly due to increased susceptibility to TB among patients with diabetes. Existing epidemiologic data demonstrate a higher prevalence of diabetes in patients with active TB compared to the background population prevalence of diabetes. However, it is unknown if the increased prevalence of diabetes among patients with active TB is due to diabetes impacting 1) risk of latent infection, 2) risk of reactivation from latent TB to active disease, 3) risk for primary progression from Mycobacterium tuberculosis exposure to active TB disease, 4) or alternatively, if TB infection or disease impacts the risk of diabetes incidence. The proposed study will help to clarify TB-diabetes pathways and will generate preliminary data useful to deconstruct the pathways which lead to increased diabetes prevalence among patients with active TB. The long term goal of the proposed work is to prepare for a prospective study to examine the relationship between TB infection and risk of diabetes and ultimately better characterize the effect of immune activity related to TB infection on metabolic function.